Progesterone Receptor Values Research Articles

Prognostic value of progesterone receptor after long-term follow-up in primary breast cancer

In a previous study of a series of 105 patients with primary breast cancer we found that the progesterone receptor (PgR) status was an important prognostic factor for early recurrences. 95 patients from the same series were followed-up for a median of 9.5 years and reassessed for the prognostic value of PgR status by univariate and multivariate statistical methods. In univariate analysis, the disease-free interval was only related to the lymphnode status. For overall survival, PgR and combined PgR-ER (oestradiol receptor) status had a prognostic value ( P = 0.035 and 0.05, respectively). Moreover, PgR status was found to be discriminant for the survival of the node-negative patients ( P = 0.017). In multivariate analysis, ER and PgR status were not significant, indicating that receptor status is not a powerful predictor of the course of breast cancer.

Steroid hormone receptor activity of primary human breast cancer and pattern of first metastasis

A series of 258 breast cancer patients with known estrogen receptor (ER) status of the primary tumour who subsequently developed metastases were reviewed for site of first metastasis. In 188 cases progesterone receptor (PgR) data were also available. Univariate analysis showed metastatic patterns to differ statistically significantly related to ER status and (less pronounced) PgR status of the primary tumour. Patients with ER-positive tumours had bone metastases three times more often than patients with ER-negative tumours. With respect to PgR-positive and PgR-negative tumours this frequency differed by a factor of two. With regard to visceral metastases ER and PgR status were equally potent prognosticators, patients with receptor negative tumours having a 50% higher frequency of visceral metastasis than patients with receptor positive tumours. Assessment of metastatic patterns in relation to combined receptor status did not substantially enhance the discriminatory value of ER and PgR when assessed separately. Multivariate analysis showed that the observed differences in metastatic patterns were all attributable to differences in the ER status of the primary tumour, and were not influenced by age, menopausal status, axillary lymph node involvement, duration of disease-free interval (DFI), mode of postoperative treatment, or the PgR status of the primary tumour.

Endocrine Factors in Common Epithelial Ovarian Cancer*

Ovarian cancer is responsible for 4% of all cancers in females and 6% of all their cancer deaths. Its mortality rate is greater than that of cervical and endometrial cancer together. The concentration of estrogen receptors (ER) rises and progesterone receptors (PR) falls in malignant ovarian tumors. In fact, ER and PR at present in 61% and 49% of malignant ovarian tumors respectively. 36% of these tumors contain both ER and PR. Further 69-90% of such tumors contain androgen receptors (AR). After (anti)hormonal agent therapy fails, physicians use progestins in combination with the synthetic antiestrogen tamoxifen in progressive or recurrent advanced ovarian cancer. The response rate for this treatment of ovarian cancer is only around 15%. Patients with malignant ovarian tumors with PR levels =or+ 50 fmol/mg tend to have a better prognosis than those with PR levels 50 fmol/mg. Neither age, stage of disease, nor tumor histology affect the prognostic value of PR. In vitro studies demonstrate that pure antiandrogens significantly inhibit about 60% of ovarian tumors. Another study also demonstrates that antiandrogen therapy alone may an effective endocrine therapy. As a result, the Gynecologic Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer if conducting a clinical trial on the effect of the antiandrogen flutamide on advanced or recurrent ovarian cancer. Researchers plan to investigate the effect of combining endocrine therapy with current standard chemotherapy. In fact, they intend to learn if combined chemo-endocrine therapy should be used as 1st line treatment for ovarian cancer.

Heterogeneity in hormone receptor status in primary and metastatic endometrial cancer

The rationale for endocrine therapy in patients with advanced endometrial carcinoma may be based on the presence of estrogen or progesterone receptors in the primary tumor. A study was designed to evaluate tumor cell heterogeneity of steroid hormone receptors in the primary and metastatic sites in endometrial cancer. Primary endometrial cancer tissue samples from 10 patients and 16 metastatic tumor sites were simultaneously analyzed for estrogen and progesterone receptors, using a radioligand biochemical assay. The primary tumor was estrogen receptor (ER) and progesterone receptor (PR) positive in 70 and 60% of the patients, respectively. The metastatic sites were ER positive in 63% and PR positive in 25%. The primary tumor tissue and the metastatic disease showed an identical ER and PR status in only 25 and 19%, respectively. Four patients had multiple metastatic sites analyzed. In two of four patients the PR values, and in three of four patients the ER values, in these metastatic sites were discordant. These data support the concept of tumor cell heterogeneity for steroid hormone receptors in endometrial cancer. To optimize treatment planning, it may be important to biopsy primary, metastatic, and recurrent tumor sites for individual analysis of receptor activity.

Variation of Estrogen and Progesterone Receptor Status in Breast Cancer after Tamoxifen Therapy

In the present paper we have studied the quantitative variations in estrogen (ER) and progesterone receptor (PR) content of breast cancer induced by tamoxifen. In addition to receptors, hormonal levels of estradiol, progesterone, prolactin, FSH, LH and testosterone were also measured. The cases included in our study were consecutively selected among those breast cancers in which an aliquot of the tissue sample sent for analysis of the steroid receptors was positive for cancer and also found to have at least one of the steroid receptors positive, not only in the biopsy but also in the surgical specimen. Following this criterion, we finally collected 14 cases of breast cancer treated daily with 30 mg of tamoxifen during an interval of 3 weeks from the initial biopsy to the final surgery. From our results we can conclude that tamoxifen reduced significantly the ER concentration while no changes were observed in PR values. Concerning hormones, while in premenopausal patients tamoxifen induced a rise in plasma estradiol, in postmenopausal women the only modification observed was a decrease in plasma FSH. The variation in steroid receptor content under tamoxifen therapy may also contribute to the evaluation of the hormone dependency of gynecologic malignancies.

P53 expression in breast cancer

Immunohistochemical evaluation of 200 primary breast cancers with the anti-p53 mouse monoclonal antibody (MAb) PAb421 showed positivity in nuclei of malignant cells in 31 cases (15.5%). PAb421+ cases were significantly more frequently epidermal growth factor receptor (EGF-R)-positive (67.7%; p less than 0.001) and estrogen receptor (ER)-negative (73.3%; p less than 0.001); they displayed surface histocompatibility class-1 (80.6%; p less than 0.01) and 11 (74.2%; p less than 0.05) antigens. Low values for progesterone receptor (mean 67.20 +/- 25.2 fmol/mg; p less than 0.05) and a high number of cells positive for the proliferation-associated antigen Ki-67 (log mean 6.88 +/- 0.33; p less than 0.01) were found in PAb421+ tumors as well as a high number of grade-3 infiltrating duct carcinomas (70%; p = 0.01). Of the 200 cases of mammary carcinoma, 88 were further analyzed using another human specific anti-p53 MAb PAb1801, and 40 (45.5%) were found positive. This MAb stained all the PAb421+ cases and was significantly associated with negative ER status (39.5%; p less than 0.05) and high Ki-67 scores (log mean 6.93 +/- 0.24; p = 0.001). Analysis of PAb1801+/Pab421- cases for HLA antigens, EGF-R and ER showed a phenotype similar to that of the p53-ve/ER+ carcinomas, except for the high Ki-67 score. No differences in age of the patient, number of involved nodes, tumor size, ploidy or labelling index scores were evident between p53+ and carcinomas. We concluded that p53 in mammary carcinomas is associated with ER-negative, growth factor receptor-positive, high-grade tumors, and is a promising new parameter to evaluate the cellular biology and prognosis of breast cancer.

A study on the correlation between estrogen receptor, progesterone receptor and tamoxifen binding sites in human breast cancer tissues.

In order to examine the clinical significance of the tamoxifen binding site, correlations between the concentration of the tamoxifen binding site and either the estrogen receptor (ER) or progesterone receptor (PgR) were studied. A saturable high-affinity tamoxifen binding site was detected in human breast cancer tissues. The concentration of the tamoxifen binding sites in 12,000 g supernatant of ER positive tumors was 122.3 +/- 186.8 (mean +/- SD) fmol/mg protein, and that of ER negative tumors was 68.38 +/- 82.97 fmol/mg protein. The concentration of the tamoxifen binding sites in 12,000 g supernatant of PgR positive tumors was 103.7 +/- 137.3 fmol/mg protein, and that in the 12,000 g supernatant of PgR negative tumors was 90.29 +/- 159.0 fmol/mg protein. There was no significant difference between the concentration of the tamoxifen binding sites in the 12,000 g supernatant of ER positive tumors and ER negative tumors, and there was no significant difference between the concentration of the tamoxifen binding sites in the 12,000 g supernatant of PgR positive tumors and PgR negative tumors. The concentration of the tamoxifen binding sites in the cytosol of PgR positive tumors was 90.55 +/- 103.5 fmol/mg protein, and that in the cytosol of PgR negative tumors was 29.13 +/- 42.22 fmol/mg protein. There was a significant difference between them (p less than 0.05). The concentration of tamoxifen binding sites in 12,000 g supernatant had no correlation with the values of ER and PgR. Only the content of tamoxifen binding sites in cytosol, and the PgR value had a significant correlation.(ABSTRACT TRUNCATED AT 250 WORDS)

Estramustine binding site in human breast cancer biopsy samples. Its relation to estrogen and progesterone receptor levels, age and menopausal status

Estramustine is a cytotoxic metabolite of estramustine phosphate (Estracyt ®), which is used in the treatment of prostatic carcinoma. An estramustine binding site (EMBS) at p H 4.8–4.9 was demonstrated in 74 of 306 (24%) breast cancer biopsy samples using isoelectric focusing in polyacrylamide gels. The presence of EMBS was significantly ( P < 0.001) correlated with negative or low estrogen and progesterone receptor values. EMBS positivity was found in 31% of the samples from pre- and perimenopausal patients and in 22% of the samples from postmenopausals. If patients were instead divided into different age groups, EMBS positivity was most frequent in samples from patients between 50 and 59 years of age (42%). With increasing age the percentage of EMBS positivity fell successively. For patients under 50 years, no difference with respect to EMBS positivity between age groups could be demonstrated. The possible value of EMBS determinations in breast cancer tissue specimens for the selection of those patients that will respond to Estracyt ® therapy should be evaluated.

Endocrine manipulation of meningiomas with medroxyprogesterone acetate. Effect of MPA on receptor status of meningioma cytosols

Fifteen patients with intracranial or spinal meningiomas have been treated with the semisynthetic progestational agent medroxyprogesterone acetate (MPA, Depo-Provera) prior to surgical removal of the tumors in order to investigate the influence of MPA on the progesterone receptor (PR) status of meningioma cytosols. MPA acted as a competitive binder to meningioma-PR: The mean PR values were 15.6 fmol/mg protein (range 0–69) and 338.3 fmol/g tumor (range 0–1190), respectively. In comparison, mean PR values of our untreated meningioma series ( n = 58) were 54.9 fmol/mg protein (range 0–586) and 2813 fmol/g tumor (range 0–17,168), respectively. In cases of two-stage resection of meningiomas MPA significantly decreased PR activity in the cytoplasm of meningioma cells. We conclude that MPA binds to meningioma PRs, however, its effect on the growth rate of meningiomas has still to be elucidated.

The effects of ischemia on estrogen and progesterone receptor profiles in the rodent uterus

Ischemia is considered to invalidate the estrogen receptor (ER) and progesterone receptor (PR) values of tissues available for steroid hormonal analysis. To evaluate the temporal effect of devascularization on steroid receptors, complete uterine ischemia was induced in vivo in 64 female Buffalo rats (80–154 g). Animals were assigned to varying intervals of ischemia (0–90 min) and were maintained at a constant ambient (75°F) and core-body temperature (100–102°F). Following tissue preservation at −80°C, multipoint titration of steroid binding capacity (SBC) was performed with [ 3H]estradiol 17-β (3–0.15 n M) or [ 3H]R5020 (8–0.4 n M) in the presence or absence of a 200-fold excess of an unlabeled ligand. Applying nonlinear regression analysis, ischemia was observed to decrease the binding capacitance for both ER and PR profiles of rodent uterine tissues at 30 min with significant decay over the 90-min interval of devascularization (ER, P < 0.01; PR, P < 0.1). Significant reduction in SBC was evident after 80 min of ischemia for PR ( P < 0.05) and 90 min of tissue ischemia for ER ( P < 0.05) comparative to control ( t 0) valves. The detrimental effect of progressive ischemia on ER and PR values was such that it appears essential to assure rapid and reliable tissue aliquot preservation techniques when organ ischemia ⩾ 90 min is anticipated.

VALIDATION OF A PROGNOSTIC INDEX IN BREAST CANCER

The validation of a prognostic index for patients with primary breast cancer is described. The actual survival data in a group of 383 patients was compared with expected survival predicted by an index based on axillary lymph node status, oestrogen receptor, progesterone receptor and age. There was no significant difference between actual and predicted deaths for five ranges of index value at 2 years and for the three highest ranges of index value at 5 years. However, in the two lowest ranges, the index significantly underpredicted deaths at 5 years. The Cox proportional hazards model was used to determine if there was any significantly better combination of coefficients and covariates to predict survival in the test group. The original index--1 = N + E + P + A, where N = 0 if no nodes are involved, 13 if one to three nodes are involved, and 31 if more than three nodes are involved; E = 15 if oestrogen receptor value is less than 10 fmol/mg cytosol protein and 0 otherwise; P = 12.5 if progesterone receptor value is less than 10 fmol/mg cytosol protein and 0 otherwise; and A = number of years over age 65--was as good as any competing model in ranking survival prospects in the test group. However, it was a less sensitive predictor in this group than in the original set of patients. A second index based on tumour size, hormone receptor status and age, for use when lymph node status was unavailable, was tested by the same method and validated.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen sulfates: biological and ultrastructural responses and metabolism in MCF-7 human breast cancer cells.

The biological effects and ultrastructural alterations by different estrogen-3-sulfates (E1-3-S and E2-3-S) and estradiol-17-sulfate (E2-17-S) were studied in the MCF-7 mammary cancer cell line in culture. The estrogen-3-sulfates very significantly stimulated the progesterone receptor (PR). The values (in pmoles/mg DNA +/- SE) were: control, 0.46 +/- 0.09; E1-3-S, 2.24 +/- 0.30, and E2-3-S, 2.56 +/- 0.45. The value of PR after E2-17-S incubation (0.56 +/- 0.24) was similar to the non-treated cells. The PR values obtained by the incubation of unconjugated estrone and estradiol were: 2.63 +/- 0.45 and 2.27 +/- 0.36, respectively. Analysis of the unconjugated estrogens in the medium indicated significant hydrolysis of estrogen-3-sulfates but not of E2-17-S. Using [3H]-E1-3-S, an important transformation was observed inside the cells, a great part being converted to estradiol (greater than 60% in the nuclear fraction). Electron microscopic examination indicated alterations in the secretory system after incubation with estrogen-3-sulfates similar to those obtained with unconjugated estradiol. The effect provoked by E2-17-S was significantly less than for the other sulfates. As estrogen sulfates are quantitatively the most important form of estrogens in the mammary gland, it is suggested that estrogen-3-sulfates play an important role in the biological responses to estrogens in breast cancer.

Breast cyst fluid proteins and breast cancer.

A specific breast cyst fluid protein was purified by the following steps: ultracentrifugation, gel filtration, DEAE and Con A chromatography, and gel filtration with guanidine, 6 M. The protein was pure, having a molecular weight of 17,800 daltons on SDS-PAGE and 68,000 daltons on gel filtration. The GCDFP 17,800 is immunologically distinct from other breast cyst fluid components and known milk and plasma proteins. A specific radioimmunoassay was developed and used to determine GCDFP 17,800 in 158 samples of breast cancer cytosol. The GCDFP 17,800 levels were significantly different between grade I tumors (mean of 813 ng protein per mg +/- 430 SEM) and grade III tumors (mean 184 ng protein per mg +/- 59 SEM) and were correlated with progesterone receptor values in postmenopausal women (Spearman's correlation, p = 0.03) but not in premenopausal women. The value of GCDFP 17,800 did not differ between the pre- and the postmenopausal women. By immunocytochemistry the intracellular localization of the GCDFP 17,800 was also found in relation to tumor grading and in correlation with PR values. GCDFP 17,800 appears as a hormone-induced protein of the breast cells. Its intracellular detection by means of radiolabeling allows a more sensitive and precise evaluation of the hormone-dependence of the breast cancer cells and emphasizes the heterogeneity of the tumor cell population.

Estrogen and progesterone receptors in intracranial tumors.

Cytoplasmic estrogen receptor (ER) and progesterone receptor (PR) proteins were measured by a dextran-coated charcoal absorption technique in 19 intracranial tumors (10 meningiomas, two acoustic neurinomas, two glioblastomas, one primary tumor of neuroectodermal origin, one hemangioblastoma, one metastasis of carcinoma, one chordoma, and one pituitary adenoma). Positive PR values (greater than or equal to 10 fmol/mg of protein) were found in nine meningiomas (90% of these tumors), in the chordoma, in one glioblastoma, and in the hemangioblastoma, whereas positive ER values were recorded only in the pituitary adenoma and in one glioblastoma. Evidence of PR in meningiomas might explain their predominance in women. A possible pharmacological therapy, based on these findings, is discussed.

Progesterone receptors and human breast cancer.

Estrogen receptor protein is known to be an important prognostic factor for patients with breast cancer. The presence of estrogen receptor correlates with response to endocrine therapy in patients with metastatic disease and is associated with prolonged disease-free and overall survival in patients with primary disease. But the correlation between estrogen receptor positivity and endocrine dependence is not perfect. Approximately 40% of estrogen receptor positive tumors fail to regress with endocrine therapy. It has been hypothesized that another protein, progesterone receptor, may be a more effective marker of endocrine responsiveness since progesterone receptor is the end product of estrogen action. We have examined the relationship between progesterone receptor and response of advanced breast cancer tumors to hormonal manipulations. Promising retrospective results indicate the need for new, prospective clinical trials to further define the prognostic value of progesterone receptor for these tumors. We have also analyzed the disease-free intervals of patients with primary disease and found that progesterone receptor was more important than estrogen receptor for predicting time to recurrence. We suggest that both estrogen receptor and progesterone receptor be routinely measured in all breast cancer tumors, and that the results of these assays will help the physician individualize therapy for breast cancer patients.

Prognostic significance of hormone receptors in early recurrence of breast cancer

A retrospective analysis of 155 patients with primary infiltrating breast cancer was carried out to determine the prognostic significance of hormone receptor values and analyze the effect of adjuvant chemotherapy. Estrogen receptor-negative patients were found to have a significantly higher recurrence rate than estrogen receptor-positive patients (p < 0.005). No difference was found based on the progesterone receptor value. The data strongly suggest a favorable response to adjuvant chemotherapy administered on the basis of the estrogen receptor value alone.

Histochemically demonstrable enzyme activities and their independence of the hormone receptor content in female breast carcinoma.

Acid phosphatase, leucine aminopeptidase, monoamine oxidase and non specific esterase activities were histochemically demonstrated in specimens derived from 15 infiltrating ductal carcinomas of female breast. The relative areas occupied by the enzyme-positive carcinoma cells were visually estimated and, in the cases of leucine aminopeptidase, assessed morphometrically. All enzyme activities were found to be subject to major variations within a single carcinoma and between individual carcinomas, and the activity of any single enzyme was independent of that of three others. None of the enzyme activities correlated with the estrogen and progesterone receptor values, nor the histological grade of malignancy of the tumour. Thus, histochemically demonstrable enzyme activities seem to be of no use in predicting the hormone receptor content in infiltrating ductal carcinomas of the female breast.

299. Pronostic value of progesterone receptor in operable breast cancer

299. Pronostic value of progesterone receptor in operable breast cancer

Estradiol and progesterone receptors in normal and neoplastic endometrium: Correlations between receptors, histopathological examinations and clinical responses under progestin therapy

AbstractHaving examined the steroid receptor (SR)' system in normal and neoplastic endometrium from pre‐and postmenopausal women, we investigated the effect of progestin therapy on estrogen and progestin receptors in neoplastic endometrium with respect to histopathological changes and clinical responses of the lesions. In normal endometrium of premenopausal women the estrogen receptor (ER) maximum occurred just before the estradiol (E) peak which is associated with a decrease in ER. In pre‐and postmenopausal women, a high progesterone receptor (PR) value was never associated with a high ER value although in postmenopausal women, PR was only detected when the ER level was high and when there was histological evidence of estrogenic influence. In neoplastic endometrium, a high degree of histological differentiation was associated with simultaneous low ER and high PR values, and vice‐versa. Progestin therapy results in virtually no change either in ER level or in pathological state of the lesions where PR was initially undetectable. In contrast, a positive clinical response was observed in a PR‐positive lesion revealing a differentiated histological type. The effect of P therapy is a fall in both ER and PR to a low level for the former and an undetectable level for the latter. The reasons for PR disappearance involve a nuclear translocation (detected 4 to 8 h after treatment) and a non‐replenishment of PR. Since the clinically responding patients were those with PR and ER positive lesions, the relationship between the presence of PR and a differentiated histological state could reflect the hormonal sensitivity of the tissue. These data also suggest that the effectiveness of P therapy is due to a redifferentiation and to a reduction of the estrogen‐dependent growth of neoplastic endometrial cells.